The invention relates generally to lactacystin and analogues thereof.
Eukaryotic cells contain multiple proteolytic systems, including lysosomal proteases, calpains, ATP-ubiquitin-proteasome dependent pathway, and an ATP-independent nonlysosomal process. The major neutral proteolytic activity in the cytosol and nucleus is the proteasome, a 20S (700 kDa) particle with multiple peptidase activities. The 20S complex is the proteolytic core of a 26S (1500 kDa) complex that degrades or processes ubiquitin-conjugated proteins. Ubquitination marks a protein for hydrolysis by the 26S proteasome complex. Many abnormal or short-lived normal polypeptides are degraded by the ubiquitin-proteasome-dependent pathway. Abnormal peptides include oxidant-damaged proteins (e.g., those having oxidized disulfide bonds), products of premature translational termination (e.g., those having exposed hydrophobic groups which are recognized by the proteasome), and stress-induced denatured or damaged proteins (where stress is induced by, e.g., changes in pH or temperature, or exposure to metals). In addition, some proteins, such as casein, do not required ubquitination to be hydrolyzed by the proteasome.
The proteasome has chymotryptic, tryptic, and peptidyl-glutamyl peptide hydrolizing activities, i.e., the proteasome can cleave peptides on the carboxyl side of hydrophobic, basic, and acidic residues, respectively.
The invention relates to novel compounds structurally related to lactacystin and lactacystin xcex2-lactone. The invention also relates to pharmaceutical compositions including lactacystin and lactacystin analogs.
One aspect of the invention is a pharmaceutical composition containing a compound having the formula 
wherein Z1 is O, S, SO2, NH, or NRa, Ra being C1-6 alkyl; X1 is O, S, CH2, two singly bonded H, CH(Rb) in the E or Z configuration, or C(Rb) (Rc) in the E or Z configuration, each of Rb and R , independently, being C1-6 alkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen, X1 being two singly bonded H when Z1 is SO2; Z2 is O, S, NH, NRd, or CHR1 in the (R) or (S) configuration, wherein Rd is C1-6 alkyl and R1 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, NRdRe, or the side chain of any naturally occurring xcex1-amino acid, or R1 and R2 taken together are a bivalent moiety, provided that when R1 and R2 are taken together, Z1 is NH or NRa and Z2 is CHR1; Re being H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl, and the bivalent moiety forming a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl, where the H in CHR1 is deleted when R1 and R2 taken together form a C3-8 heteroaryl or C6-12 aryl; R2 is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, azido, C2-6 alkynyl, halogen, ORf, SRf, NRfRg, xe2x80x94ONRfRg, xe2x80x94NRg(ORf), or xe2x80x94NRg(SRf) (each of Rf and Rg, independently, being H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl), or R1 and R2 taken together are a bivalent moiety, the bivalent moiety forming a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl, where the H in CHR1 is deleted when R1 and R2 taken together form a C3-8 heteroaryl or C6-12 aryl; A1 is H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRi, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Ri, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)-oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; X2 is O or S; and LO is an organic moiety having 1 to 25 carbon atoms, 0 to 10 heteroatoms, and 0 to 6 halogen atoms; and a pharmaceutically acceptable carrier.
A second aspect is a pharmaceutical composition comprising a compound having the following formula 
wherein Z1 is O, S, SO2, NH, or NRa, Ra being C1-6 alkyl; X1 is O, S, CH21 two singly bonded H, CH(Rb) in the E or Z configuration, or C(Rb) (Rc) in the E or Z configuration, each of Rb and Rc, independently, being C1-6 alkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen, provided that when Z1 is SO2, X1 is two singly bonded H; Z2 is CHR1 in the (R) or (S) configuration, R1 being H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, halogen, a side chain of a naturally occuring xcex1-amino acid, ORd, SRd, or NRdRe (each of Rd and Re, independently, being H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-5 alkynyl); Z3 is O, S, NH, or NRj, wherein Rj is C1-6 alkyl; X2 is O or S; and A1 is H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)-oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
A third aspect is a pharmaceutical composition comprising a compound having one of the following formulae 
wherein Z1 is NH or NRa, Ra being C1-6 alkyl; X1 is O, S, CH2, two singly bonded H, CH(Rb) in the E or Z configuration, or C(Rb) (Rc) in the E or Z configuration, each of Rb and Rc, independently, being C1-6 alkyl, C6-2 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen; Z2 is O, S, NH, or NRj, wherein Rj is C1-6 alkyl; R1 is in the (R) or (S) configuration, and is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, halogen, a side chain of a naturally occuring xcex1-amino acid, ORd, SRd, or NRdRe (each of Rd and Re, independently, being H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen); X2 is O or S; and A1 is H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)-oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
A fourth aspect is a pharmaceutical composition containing a compound having the following formula 
wherein Z1 is O, S, NH or NRj, Rj being C1-6 alkyl; X1 is O or S; R1 is in the (R) or (S) configuration, and is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, halogen, a side chain of a naturally occuring xcex1-amino acid, ORd, SRd, or NRdRe (each of Rd and Re, independently, being H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-5 alkynyl); R2 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, C3-8 heteroaryl, or halogen; X2 is O or S; and A1 is H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh) or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)-oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
A fifth aspect is a pharmaceutical composition comprising a compound having the following formula 
wherein Z1 is O, S, NH or NRj, Rj being C1-6 alkyl; X1 is O or S; R1 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, halogen, a side chain of a naturally occuring xcex1-amino acid, ORd, SRd, or NRdRe (each of Rd and Re, independently, being C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen); R2 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, C3-8 heteroaryl, or halogen; Ra is C1-6 alkyl; and A1 is H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)-oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
A sixth aspect is a pharmaceutical composition containing a compound having the formula 
wherein X1 is O, S, CH2, two singly bonded H, CH(Rb) in the E or Z configuration, or C(Rb) (Rc) in the E or Z configuration, each of Rb and Rc, independently, being C1-6 alkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen; Z1 is O, S, NH, or NRa, Ra being C1-6 alkyl; R1 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, halogen, a side chain of any naturally occuring xcex1-amino acid, ORd, SRd, or NRdRe (each of Rd and Re, independently, being H, C1-6 alkyl, C1-6 halo-alkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen); or R1 and R2 taken together are a bivalent moiety which forms a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl; R2 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, azido, C2-6 alkynyl, halogen, ORf, SRf, NRfRg, xe2x80x94ONRfRg, xe2x80x94NRg(ORf), or NRg(SRf) (each of Rf and Rg, independently, being H, C1-6, alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl), or R1 and R2 taken together are a bivalent moiety, the bivalent moiety forming a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl;
X2 is O or S; and A1 is in the (R) or (S) configuration, and each of A1 and A2 is independently H, the side chain of any naturally occurring amino a-acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
A seventh aspect is a pharmaceutical composition containing a compound having the following formula 
wherein Z1 is NH or NRa, NRa being C1-6 alkyl;
X1 is O, S, CH2, two singly bonded H, CH(Rb) in the E or Z configuration, or C(Rb) (Rc) in the E or Z configuration, each of Rb and Rc, independently, being C1-6 alkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen;
Z2 is O, S, NH, or NRj, Rj being C1-6 alkyl;
R1 is in the (R) or (S) configuration, and is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, halogen, a side chain of any naturally occuring amino acid, ORd, SRd, or NRdRe (each of Rd and Re, independently, being H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or halogen); or R1 and R2 taken together are a bivalent moiety which forms a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl; R2 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, azido, C2-6 alkynyl, halogen, ORf, SRf, NRfRg, xe2x80x94ONRfRg, xe2x80x94NRg(ORf), or xe2x80x94NRg(SRf) (each of Rf and Rg, independently, being H, C1-6, alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl), or R1 and R2 taken together are a bivalent moiety, the bivalent moiety forming a C3-8 cycloalkyl, C3-8 heteroaryl, C3-8 heterocyclic radical, or C6-12 aryl; X2 is O or S; and each of A1 and A2 is independently in the (R) or (S) configuration, and is independently H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Y(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRi, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
An eighth aspect is a pharmaceutical composition containing a compound of the formula 
wherein Z1 is O, NH, or NRa, NRa being C1-6 alkyl; X1 is O, S, CH2, or two singly bonded H; each of A1 and A2 is independently H, the side chain of any naturally occurring xcex1-amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and R12 is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl; and a pharmaceutically acceptable carrier.
A ninth aspect is a pharmaceutical composition comprising a compound having the formula 
wherein Z1 is NH, or NRa t NRa being C1-6 alkyl; each of X1 and X2, independently, is O or S; each of A1 and A2 is independently in the (R) or (S) configuration, and is independently H, the side chain of any naturally occurring amino acid, or is of the following formula,
xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)nxe2x80x94R3X3
wherein Y is O, S, Cxe2x95x90O, Cxe2x95x90S, xe2x80x94(CHxe2x95x90CH)xe2x80x94, vinylidene, xe2x80x94Cxe2x95x90NORh, xe2x80x94Cxe2x95x90NNRiRixe2x80x2, sulfonyl, methylene, CHX4 in the (R) or (S) configuration, or deleted, X4 being halogen, methyl, halomethyl, ORh, SRh, NRiRixe2x80x2, xe2x80x94NRi(ORh), or xe2x80x94NRi(NRiRixe2x80x2), wherein Rh is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, and each of Ri and Rixe2x80x2, independently is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-10 acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R3 is straight chain or branched C1-8 alkylidene, straight chain or branched C1-8 alkylene, C3-10 cycloalkylidene, C3-10 cycloalkylene, phenylene, C6-14 arylalkylidene, C6-14 arylalkylene, or deleted, and X3 is H, hydroxyl, thiol, carboxyl, amino, halogen, (C1-6 alkyl)oxycarbonyl, (C7-14 arylalkyl)oxycarbonyl, or C6-14 aryl; or R3 and X3 taken together are the side chain of any naturally occurring xcex1-amino acid; and a pharmaceutically acceptable carrier.
Many of the compounds described above are novel compounds; the novel compounds are also claimed. The invention also encompasses lactacystin analogues that can be made by the synthetic routes described herein, and methods of treating a subject having a condition mediated by proteins processed by the proteasome by administering an effective amount of a pharmaceutical composition containing a compound disclosed herein to the subject.
The compounds disclosed herein are highly selective for the proteasome, and do not inhibit other proteases such as trypsin, xcex1-chymotrypsin, calpain I, calpain II, papain, and cathepsin B.
Other features or advantages of the present invention will be apparent from the following detailed description, and also from the appending claims.